权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neddylation and cardiac protein quality control

Neddylation 和心脏蛋白质量控制

基本信息

批准号：
10311044
负责人：
Huabo Su
金额：
$ 45.1万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311044
关键词：
Address Adult Adverse event Animal Model Animals Attenuated Biochemical Bioenergetics Biological Biological Assay Cancer Patient Cardiac Cardiac Myocytes Cardiac development Cardiac health Cardiomyopathies Cardiotoxicity Cell Death Cell physiology Cells Cessation of life Clinical Trials Congestive Heart Failure Cullin Proteins Data Development Dilated Cardiomyopathy Disease Enzymes Equilibrium Functional disorder Funding Goals Grant Guanosine Triphosphate Phosphohydrolases Health Heart Heart Diseases Heart failure Homeostasis Human ISG15 gene Impairment Investigation Laboratories Maintenance Mediating Membrane Potentials Mitochondria Modification Molecular Morphology Mus Myocardial dysfunction Neonatal Non-compaction cardiomyopathy Oncology Organ Parkin Pathologic Pathology Pathway interactions Patients Performance Perinatal Perinatal mortality demographics Personal Satisfaction Pharmacology Phenotype Physiology Play Post-Translational Protein Processing Proteins Proteome Publishing Quality Control Regenerative capacity Regulation Research Respiration Rest Role Stress Testing Time Tissues Ubiquitin Ubiquitin Like Proteins Ubiquitination Ventricular cancer therapy combat conditional knockout heart function inhibitor innovation insight live cell imaging mitochondrial dysfunction mitochondrial fitness mitochondrial membrane novel organ growth pre-clinical premature pressure proteostasis restoration ubiquitin ligase

项目摘要

PROJECT SUMMARY Disruption of protein homeostasis causes cardiomyocyte (CM) dysfunction and death, and is increasingly recognized to play a causal role in human cardiomyopathies and heart failure. Ubiquitin (Ub) and Ub-like proteins modify diverse protein substrates and expand the functional diversity of the proteome. An extensive body of work has suggested the exciting potential of targeting these protein modifiers to combat cardiac disease. However, the functional role of NEDD8, a novel Ub-like protein, remains poorly understood in the heart. Neddylation covalently attaches NEDD8 to target proteins via NEDD8-specific E1-E2-E3 enzymes. Over the previous funding cycle, we discovered that neddylation is dysregulated in the failing hearts of patients and animal models of cardiac diseases. We further demonstrated that a balance between neddylation and deneddylation is essential to cardiac homeostasis, as evidenced by the fact that perturbation of deneddylation precipitated the heart to cardiomyopathy and heart failure, whereas blockade of neddylation in the developing heart caused ventricular noncompaction and perinatal lethality. Although it is becoming apparent that neddylation is essential for organ development, its functional importance in fully differentiated, postmitotic tissues is not clear. This grant addresses a novel linkage between neddylation and mitochondrial integrity in adult CMs. Pharmacological inhibition of neddylation promoted mitochondrial fusion, disrupted mitochondrial membrane potential and impaired mitochondrial respiration in neonatal CMs. Deletion of NAE1 (a regulatory subunit of the NEDD8 E1 enzyme) in adult CMs also resulted in mitochondrial elongation and impaired mitochondrial quality. Mechanistically, neddylation modifies various cellular proteins to regulate mitochondrial dynamics and mitophagy. Conditional knockout (KO) of NAE1 in adult mouse hearts resulted in dilated cardiomyopathy, heart failure, and ultimately premature death. In clinical trials, administration of the neddylation inhibitor MLN4924 to cancer patients elicited severe cardiotoxicity. These compelling published and preliminary data form the basis of our central hypothesis that neddylation is required for normal heart function through regulation of mitochondrial dynamics and mitophagy. Using the newly generated inducible NAE1KO mice and MLN4924, Aim 1 will establish the significance of neddylation in the adult healthy and failing heart and determine the impact of neddylation on mitochondrial function. Aim 2 will dissect the molecular basis by which neddylation controls mitochondrial dynamics and will test if normalization of mitochondrial morphology benefits the NAE1KO heart. Aim 3 will elucidate novel Parkin-independent mechanisms by which neddylation regulates mitophagy and test whether restoration of neddylation attenuates cardiac dysfunction in NAE1KO mice. This study will be the first to establish an unappreciated role for neddylation in regulating mitochondrial fitness and function in adult CMs. Moreover, it will provide novel insight into the potential cardiotoxicity of neddylation inhibitors that are currently being applied in cancer therapy, thus advancing the field of cardio-oncology.

项目概要蛋白质稳态的破坏会导致心肌细胞 (CM) 功能障碍和死亡，并且这种情况日益严重公认在人类心肌病和心力衰竭中发挥因果作用。泛素 (Ub) 和 Ub 样蛋白修饰不同的蛋白质底物并扩大蛋白质组的功能多样性。大量的工作表明了针对这些蛋白质修饰剂来对抗心脏病的令人兴奋的潜力。然而， NEDD8（一种新型 Ub 样蛋白）在心脏中的功能作用仍知之甚少。内基化通过 NEDD8 特异性 E1-E2-E3 酶将 NEDD8 共价连接到靶蛋白上。较前期资金循环中，我们发现 neddylation 在衰竭心脏患者和动物模型中失调心脏病。我们进一步证明，neddylation 和 deneddylation 之间的平衡至关重要对心脏稳态的影响，事实证明，去甲基化的扰动会促使心脏心肌病和心力衰竭，而发育中的心脏中的neddylation的阻断会导致心室不致密化和围产期致死率。尽管 neddylation 对器官至关重要发育，其在完全分化的有丝分裂后组织中的功能重要性尚不清楚。这笔赠款地址成人 CM 中 neddylation 和线粒体完整性之间的新联系。药理抑制 neddylation 促进线粒体融合，破坏线粒体膜电位并受损新生儿 CM 中的线粒体呼吸。删除 NAE1（NEDD8 E1 酶的调节亚基）成人 CM 还会导致线粒体伸长和线粒体质量受损。从机械上来说， neddylation 修饰各种细胞蛋白以调节线粒体动力学和线粒体自噬。有条件的成年小鼠心脏中 NAE1 的敲除（KO）导致扩张型心肌病、心力衰竭，并最终导致过早死亡。在临床试验中，对癌症患者施用 neddylation 抑制剂 MLN4924 引发了严重的心脏毒性。这些令人信服的已发表的初步数据构成了我们中心假设的基础 neddylation 是通过调节线粒体动力学来维持正常心脏功能所必需的线粒体自噬。使用新生成的可诱导 NAE1KO 小鼠和 MLN4924，目标 1 将建立 neddylation 对成人健康和衰竭心脏的重要性，并确定 neddylation 对健康和衰竭心脏的影响线粒体功能。目标 2 将剖析 neddylation 控制线粒体的分子基础动力学并将测试线粒体形态正常化是否有益于 NAE1KO 心脏。目标3将阐明 neddylation 调节线粒体自噬的新的 Parkin 独立机制，并测试是否恢复neddylation可减轻NAE1KO小鼠的心脏功能障碍。这项研究将首次建立 neddylation 在调节成人 CM 线粒体健康和功能中的作用未被认识到。而且，它将为目前正在应用的neddylation抑制剂的潜在心脏毒性提供新的见解癌症治疗，从而推进了心脏肿瘤学领域。